PMID- 28904197
OWN - NLM
STAT- MEDLINE
DCOM- 20171206
LR  - 20180515
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 23
DP  - 2017 Dec 1
TI  - Differential Inhibitory Receptor Expression on T Cells Delineates Functional
      Capacities in Chronic Viral Infection.
LID - e01263-17 [pii]
LID - 10.1128/JVI.01263-17 [doi]
AB  - Inhibitory receptors have been extensively described for their importance in
      regulating immune responses in chronic infections and cancers. Blocking the
      function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 has 
      shown promise for augmenting CD8 T cell activity and boosting pathogen-specific
      immunity. However, the prevalence of inhibitory receptors on CD4 T cells and
      their relative influence on CD4 T cell functionality in chronic HIV infection
      remains poorly described. We therefore determined and compared inhibitory
      receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on
      virus-specific CD4 and CD8 T cells in relation to their functional T cell
      profile. In chronic HIV infection, inhibitory receptor distribution differed
      markedly between cytokine-producing T cell subsets with, gamma interferon
      (IFN-gamma)- and tumor necrosis factor alpha (TNF-alpha)-producing cells
      displaying the highest and lowest prevalence of inhibitory receptors,
      respectively. Blockade of inhibitory receptors differentially affected cytokine
      production by cells in response to staphylococcal enterotoxin B stimulation.
      CTLA-4 blockade increased IFN-gamma and CD40L production, while PD-1 blockade
      strongly augmented IFN-gamma, interleukin-2 (IL-2), and TNF-alpha production. In 
      a Friend retrovirus infection model, CTLA-4 blockade in particular was able to
      improve control of viral replication. Together, these results show that
      inhibitory receptor distribution on HIV-specific CD4 T cells varies markedly with
      respect to the functional subset of CD4 T cells being analyzed. Furthermore, the 
      differential effects of receptor blockade suggest novel methods of immune
      response modulation, which could be important in the context of HIV vaccination
      or therapeutic strategies.IMPORTANCE Inhibitory receptors are important for
      limiting damage by the immune system during acute infections. In chronic
      infections, however, their expression limits immune system responsiveness.
      Studies have shown that blocking inhibitory receptors augments CD8 T cell
      functionality in HIV infection, but their influence on CD4 T cells remains
      unclear. We assessed the expression of inhibitory receptors on HIV-specific CD4 T
      cells and their relationship with T cell functionality. We uncovered differences 
      in inhibitory receptor expression depending on the CD4 T cell function. We also
      found differences in functionality of CD4 T cells following blocking of different
      inhibitory receptors, and we confirmed our results in a Friend virus retroviral
      model of infection in mice. Our results show that inhibitory receptor expression 
      on CD4 T cells is linked to CD4 T cell functionality and could be sculpted by
      blockade of specific inhibitory receptors. These data reveal exciting
      possibilities for the development of novel treatments and immunotherapeutics.
CI  - Copyright (c) 2017 American Society for Microbiology.
FAU - Teigler, Jeffrey E
AU  - Teigler JE
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Zelinskyy, Gennadiy
AU  - Zelinskyy G
AD  - Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 
      Essen, Germany.
FAU - Eller, Michael A
AU  - Eller MA
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Bolton, Diane L
AU  - Bolton DL
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Marovich, Mary
AU  - Marovich M
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
AD  - NIAID, National Institutes of Health, Bethesda, Maryland, USA.
FAU - Gordon, Alexander D
AU  - Gordon AD
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Alrubayyi, Aljawharah
AU  - Alrubayyi A
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Alter, Galit
AU  - Alter G
AD  - Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Robb, Merlin L
AU  - Robb ML
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
FAU - Martin, Jeffrey N
AU  - Martin JN
AD  - Department of Epidemiology and Biostatistics, University of California, San
      Francisco, California, USA.
FAU - Deeks, Steven G
AU  - Deeks SG
AD  - UCSF School of Medicine, University of California, San Francisco, California,
      USA.
FAU - Michael, Nelson L
AU  - Michael NL
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA.
FAU - Dittmer, Ulf
AU  - Dittmer U
AD  - Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 
      Essen, Germany.
FAU - Streeck, Hendrik
AU  - Streeck H
AD  - U.S. Military HIV Research Program, Walter Reed Army Institute of Research,
      Silver Spring, Maryland, USA hendrik.streeck@uk-essen.de.
AD  - Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.,
      Bethesda, Maryland, USA.
AD  - Institute for HIV Research, University Hospital Essen, University Duisburg-Essen,
      Essen, Germany.
LA  - eng
GR  - P30 AI027763/AI/NIAID NIH HHS/United States
GR  - R01 AI091450/AI/NIAID NIH HHS/United States
GR  - R01 AI094602/AI/NIAID NIH HHS/United States
GR  - TL1 TR001069/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20171114
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (Antibodies)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (CTLA4 protein, human)
RN  - 0 (Costimulatory and Inhibitory T-Cell Receptors)
RN  - 0 (Cytokines)
RN  - 0 (Enterotoxins)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Pdcd1 protein, mouse)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 39424-53-8 (enterotoxin B, staphylococcal)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Animals
MH  - Antibodies/administration & dosage/pharmacology
MH  - CD4-Positive T-Lymphocytes/drug effects/*immunology/virology
MH  - CTLA-4 Antigen/antagonists & inhibitors/genetics/immunology
MH  - Costimulatory and Inhibitory T-Cell Receptors/*antagonists & inhibitors/drug
      effects/*genetics
MH  - Cytokines/biosynthesis/drug effects
MH  - Enterotoxins/pharmacology
MH  - Friend murine leukemia virus/physiology
MH  - *Gene Expression
MH  - HIV Infections/*immunology/virology
MH  - Humans
MH  - Interferon-gamma/biosynthesis
MH  - Mice
MH  - Programmed Cell Death 1 Receptor/antagonists & inhibitors/genetics/immunology
MH  - Retroviridae Infections/immunology
MH  - Tumor Necrosis Factor-alpha/biosynthesis
PMC - PMC5686724
OTO - NOTNLM
OT  - *CD4 T cells
OT  - *CTLA-4
OT  - *HIV
OT  - *PD-1
OT  - *inhibitory receptors
EDAT- 2017/09/15 06:00
MHDA- 2017/12/07 06:00
CRDT- 2017/09/15 06:00
PHST- 2017/07/28 00:00 [received]
PHST- 2017/08/24 00:00 [accepted]
PHST- 2017/09/15 06:00 [pubmed]
PHST- 2017/12/07 06:00 [medline]
PHST- 2017/09/15 06:00 [entrez]
AID - JVI.01263-17 [pii]
AID - 10.1128/JVI.01263-17 [doi]
PST - epublish
SO  - J Virol. 2017 Nov 14;91(23). pii: JVI.01263-17. doi: 10.1128/JVI.01263-17. Print 
      2017 Dec 1.